Oxaliplatin is one of the most widely used anticancer agents, specifically for the treatment of advanced colorectal cancer carcinomas. The clinical use of oxaliplatin is associated with dose-limiting damage to peripheral nerves (neurotoxicity), which occurs in up to 90% of patients despite intensive prophylactic measures, and this complication may limit further treatment or even threaten life. There is currently no known specific treatment for oxaliplatin-induced peripheral neurotoxicity, and mechanistic details of this side effect have remained poorly studied. We have recently found that the urinary excretion of oxaliplatin and drug- induced damage to dorsal root ganglia cells is dependent on organic cation transporter-mediated transport. In mice, this process was found to be regulated by the two closely related organic cation transporters, Oct1 and Oct2, that are functionally redundant and that together fulfill a role equivalent to that of a single organic cation transporter, OCT2, in humans. These transporters are highly expressed on the basolateral membrane of renal tubular and dorsal root ganglia cells, and their function can be modulated by various tyrosine kinase inhibitors through a non-competitive mechanism. Moreover, we found that OCT2 is essentially absent in human colorectal cancer cell lines and human colorectal tumors, suggesting that OCT2 is unlikely to play a role in the transport of oxaliplatin into tumor cells in vivo. In the current proposal, we outline three sets of related studies that will further test and refine the validity of our central hypothesis that targeted inhibition of OCT2 function will specifically affect oxaliplatin accumulation in dorsal root ganglia and its downstream toxic effects. (1) Using various in vitro and in vivo models, we will further determine the qualitative and quantitative effects of tyrosine kinase inhibitors, including dasatinib, on the function of OCT2. (2) Studies will be performed to determine the effect of tyrosine kinase inhibitors as in vivo modulators of acute and chronic oxaliplatin-induced neurotoxicity. (3) Additional studies in nu/nu mice bearing human colorectal tumor xenografts with variable expression levels of OCT2 will determine the direct contribution of this transporter to oxaliplatin-related anticancer efficacy, and the effects of concurrent OCT2 inhibitors. The demonstration of reduced oxaliplatin-induced neurotoxicity through inhibition of a critical transporter regulating access of the drug to dorsal root ganglia will provide the foundatin for additional studies in the future aimed at ameliorating this debilitating side effect in routine clinical practice.
Oxaliplatin is among the most effective and widely prescribed anticancer agents but its clinical use is associated with dose-limiting, irreversible damage to peripheral nerves (neurotoxicity). Using a unique genetic mouse model, we found that oxaliplatin neurotoxicity is dependent on transporter-mediated drug uptake into dorsal root ganglia cells. Our proposed studies are of direct human relevance because targeted interference with the identified transport system may mitigate the incidence and severity of this debilitating side effect in humans.
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| Sprowl, Jason A; Ong, Su Sien; Gibson, Alice A et al. (2016) A phosphotyrosine switch regulates organic cation transporters. Nat Commun 7:10880 |
